在急性髓性白血病中,ENL将基因乙化与致癌基因表达联系在一起
Liling Wan1,2,3, Hong Wen4,5, Yuanyuan Li6,7
1Laboratory of Chromatin Biology &Epigenetics, The Rockefeller University, New York, New York 10065, USA.
Nature
|February 28, 2017
概括
对于急性髓性白血病 (AML) 的进展来说,ENL蛋白非常重要. 向ENL,一个基因组乙化读取器,显示抗白血病效果,并增强BET抑制剂的疗效,提供一种新的表观遗传疗法策略.
科学领域:
- 表观遗传学
- 分子生物学
- 癌症研究
背景情况:
- 异常的表观遗传场景驱动癌症,读者蛋白质的基因组修饰识别是关键机制.
- 代蛋白和额外终端 (BET) 抑制剂是针对这些途径的临床前景.
- 人类癌症中YEATS域的功能作用以前是未知的.
研究的目的:
- 在急性髓性白血病 (AML) 中研究 YEATS 域含有蛋白质 ENL 的功能重要性.
- 确定ENL是否在维持AML中发挥作用,以及是否可以针对其治疗效益.
主要方法:
- 在AML模型中通过CRISPR-Cas9调解ENL的耗尽.
- 生物化学测定,晶体结构研究和染色体免疫沉,然后进行测序 (ChIP-seq).
- 基于结构的突变发生,以破坏ENL的YEATS域与基因素乙化相互作用.
主要成果:
- 在体外和体内,ENL衰竭显示出抗白血病作用,包括骨髓分化和抑制白血病生长.
- 鉴定出ENL是一种基因素H3乙化读取物,与H3K27ac和H3K9ac共同定位在AML必需的活性基因促进物上.
- 干扰ENL的YEATS域相互作用损害了RNA聚合酶II的招募和抑制瘤基因表达,使细胞对BET抑制剂敏感.
结论:
- 在急性髓性白血病中,ENL是一个关键的基因素乙化读取器,调节瘤转录程序.
- 通过将其从染色质中取代来向ENL是一种潜在的表观遗传疗法.
- 使用ENL破坏和BET抑制剂的联合治疗可能会提高AML治疗的疗效.
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